This program project grant focuses on the interplay between pathogens and the immune system using mice and several intracellular pathogens as the experimental system. The proposal takes advantage of recent advances in microarray, imaging and mouse transgenic/knockout technologies. We will utilize previously available knock-out and transgenic mouse strains, as well as those recently made in Berkeley (Core B) to explore the role of specific molecules and cells during immune responses and to tag cells with fluorescent labels in vivo. The latter will be crucial for the 2-photon imaging studies (Core C) that make it possible to track pathogens and immune cells within tissues in real time. The microarray technology allows us to assess global gene expression and to examine host responses in infected cells. The investigators in this proposal are a strong, interactive group of immunologists and microbiologists (5 PI/co-PI), who are actively investigating host-pathogen interactions. The three projects with many proposed collaborative experiments are: Initiation of immune responses to Toxoplasma gondii (Project 1), The role of "apoptotic proteins" in regulation of innate immunity (Project 2) and Induction of NK cell ligands by viruses (Project 3). The projects will examine the host response of wild-type and selected mutant mice/cells to several NIAID priority pathogens (Toxoplasma gondii, Influenza, Vaccinia, Lymphocytic Choriomeningitis virus) and other pathogens (Murine &Human cytomegalovirus, Murine herpes virus 68, Moloney Murine Leukemia Virus, Kaposi's Sarcoma Herpes Virus, Mouse Hepatitis Virus, Mouse Adeno Virus, Polyomavirus). The planned experiments will not only provide fundamental insights into how the immune system responds to pathogenic infection but should also aid in the design of effective vaccines and drugs for prevention and treatment of bioterrorism agents and emerging infectious diseases.